Naltrexone and the Treatment of Alcohol Dependence.

There currently is a great demand for effective medications to reduce the high relapse rates that occur in the early stages of treatment for alcohol dependence. Recent clinical trials of the opiate antagonist naltrexone have shown that this medication significantly decreases excessive alcohol drinking.


EXPERIMENTAL BACKGROUND
F o r o n e q u a r t e r o f a c e n t u r y , r e s e a r c h e r s h a v e s h o w n t h a t a l c o h o l c o n s u m p t i o n c a n a l t e r t h e a c t i v i t y o f o p i a t e r e c e p t o r s ( C o h e n a n d C o l l i n s 1 9 7 0 ; D a v i s a n d W a l s h 1 9 7 0 ) . T h e s e r e c e p t o r s e x i s t i n t h e b r a i n a n d n o r m a l l y a r e s t i m u l a t e d b y n a t u r a l l y o c c u r r i n g s u b s t a n c e s ( drugs, such as alcohol, may enhance opiate receptor activity indirectly, perhaps by stimulating the release of endogenous opioids. In support of this theory, animal studies have demonstrated important interactions between alcohol consumption and increases in opiate receptor activity. Specifically, alcohol consumption stimu lates opiate receptor activity; is influenced by the use of opiates, such as morphine; and is reduced by opiate antagonists, such as naltrexone (figure 1). Each of these findings is described below.

Alcohol's Effects on Opiate Receptor Activity
Several mechanisms by which alcohol may indirectly affect opiate receptor activity have been suggested, but the one presented here appears most important in under standing alcohol dependence. Accumulating evidence, including studies in humans, shows that alcohol stimulates the release of endogenous opioids, such as beta endorphin, normally used by the body to mitigate pain, and other endorphins that produce pleasurable effects (see reviews by Gianoulakis 1993;Volpicelli et al. 1994).
This release of endorphins may ex plain why some strains of rats and some people drink excessive amounts of alco hol. For example, rats bred to have a high preference for alcohol show enhanced betaendorphin release when they con sume alcohol compared with rats bred for a low preference for alcohol (deWaele et al. 1992). Similarly, in a study conduct ed by Gianoulakis and colleagues (1990), male social drinkers who were at increased risk for alcohol abuse, because they had alcoholdependent parents, experienced a 170percent increase in peripheral betaendorphin levels after consuming a moderate dose of alcohol. In contrast, male social drinkers without alcohol dependent parents did not show any in crease in betaendorphin levels after drinking the same amount of alcohol. Thus, enhanced release of endorphins induced even by small amounts of alcohol may increase the risk for alcohol abuse, and the more a person drinks, the more endorphins appear to be released.

Opiate Effects on Alcohol Consumption
Many studies show that the administration of opiates affects alcohol consumption (see table 1). For example, rats given a single 30 milligrams per kilogram (mg/kg) mor phine injection (a high dose) decreased their alcohol but not their water consump tion, demonstrating that morphine's effect was restricted to alcohol (Sinclair 1974). Ho and colleagues (1976) also found that rats decreased their alcohol consumption in inverse proportion to their morphine dose. In this study, rats given an incremental dose regimen (i.e., 10, 30, 60 mg/kg) of morphine showed a corresponding de crease in alcohol consumption.
Although opiate use can reduce prefer ence for alcohol, preference dramatically increases during opiate withdrawal. For example, Volpicelli and colleagues (1991) found that rats with free access to both alcohol and water decreased their alcohol consumption, compared with control rats, when injected with morphine. The day after receiving the injections, however, the morphineinjected rats drank approxi mately twice as much alcohol as the control rats (figure 2). These results fur ther support an inverse relationship be tween opiate receptor activity and alcohol consumption. An increase in activity at opiate receptors causes a decrease in alcohol consumption, whereas subsequent opiate withdrawal causes an increase in alcohol consumption.
An important exception to this rela tionship comes from the research con ducted by Reid and associates (1991), in which small doses of morphine were found to increase alcohol drinking tran siently in rats given limited access to alcohol or water. For example, rats with 2hour access to alcohol or water that received a low dose of morphine (general ly less than 2.5 mg/kg) typically drank more of an alcohol solution than did rats injected with saline.
The effect of small doses of opioids to increase alcohol drinking is similar to receiving an appetizer before dinner. A small amount of a pleasurable substance can increase the motivation to consume more of that substance. This appetizer, or priming, effect has been observed across a variety of addictive drugs. For example, rats that have stopped signaling (by press ing a bar) to obtain cocaine will respond again after receiving a small dose of co caine (Stewart 1983). Similarly, human cocainedependent patients often report that sampling cocaine enhances the motivation Table 1 Alcohol produces some of its effects by interacting with opiate receptors in the brain, which normally are activated in response to pain by naturally occurring substances called opioids. Substances that mimic opioid function, such as morphine, are studied to elucidate alcoholʼs interaction with this system. These studies offer evidence of the contradictory effects of high and low doses of opioids on alcohol consumption in rats as well as the effects of opiate antagonists, substances that block opiate receptors, on alcohol consumption. In general, higher doses of opioids decreased alcohol consumption by the rats, whereas low doses increased consumption. Doses of opioid antagonists, in contrast, decreased alcohol consumption regardless of the dose amount.  Ho et al. (1976) Morphine 10, 30, 60 mg/kg Decreased alcohol consumption Reid et al. (1987) Morphine 7.5, 20.0 mg/kg Decreased alcohol intake Ross et al. (1976) Morphine sulfate 7.5 mg/kg Decreased alcohol intake Sinclair et al. (1974) Morphine 30 mg/kg Decreased alcohol intake Volpicelli et al. (1991) Morphine 10.0 mg/kg Decreased alcohol intake  Reid et al. (1991) Morphine 2.0 mg/kg Increased alcohol intake
2 All terms in this column reflect how the drug given altered the animalsʼ alcohol intake. The specific terminology is used in each case as it was in the study. 3 Animals in this study were trained to perform a task, or to respond, to receive an intravenous dose of alcohol.
to use more cocaine, creating a vicious addictive cycle (Jaffe et al. 1989). A similar addictive cycle may occur in animals or humans who drink alcohol excessively. Like the injection of a small dose of morphine, alcohol consumption may lead to modest increases in opiate receptor activity. This heightened opiate receptor activity primes, or enhances, the motivation to drink more alcohol. Thus a vicious cycle could be established for people at risk for developing alcohol abuse. These people (such as the highrisk subjects mentioned above in the study by Gianoulakis and colleagues [1990]) may find that one drink increases the motiva tion and craving for the next drink, and this may explain why some alcohol dependent people find it difficult to con trol their alcohol consumption once they have begun to drink. This mechanism also suggests that the use of an opiate receptor blocker, such as naltrexone, could break the vicious cycle and thus reduce exces sive alcohol consumption. (Table 1 sum marizes studies that further demonstrate the contradictory effects of opioids on alcohol consumption in animals.)

Opiate Antagonist Effects on Alcohol Consumption
An extensive body of literature shows that compounds blocking opiate receptorsopiate antagonists-reduce alcohol drink ing in animals (table 1). Many of these studies have been performed using nalox one, a shortacting, injected opiate antag onist. For example, MarfaingJallat and colleagues (1983) found that naloxone reduces alcohol preference in rats given a choice between water and alcohol. Numer ous researchers have replicated these results in a variety of studies (e.g., Samson and Doyle 1985;Froehlich et al. 1990).
Several animal studies also have used the opiate antagonist naltrexone to reduce alcohol consumption. Naltrexone is a longer acting compound developed from naloxone that is used as a treatment for opiate addiction. For example, Altshuler and colleagues (1980) found that naltrexone decreased alcohol intake among rhesus monkeys trained to press levers to obtain doses of intravenous alcohol. Similarly, in a rat model of stressinduced excessive alco hol consumption, researchers found that naltrexone injections completely blocked the animals' stressinduced increases in alcohol consumption (Volpicelli et al. 1986).

NALTREXONE STUDIES IN ALCOHOLDEPENDENT PEOPLE
The preclinical research studies discussed above have served as the impetus to test naltrexone in the treatment of alcohol dependent patients. Overall, animal stud ies suggest that alcohol produces impor tant pharmacological effects that enhance opiate receptor activity, that opiate recep tor activity can influence the desire to drink alcohol, and that opiate antagonists can block alcohol's rewarding effects.

The Volpicelli Study
To determine naltrexone's efficacy in reducing rates of relapse in alcohol dependent people, Volpicelli and col leagues (1992) performed a 12week, doubleblind clinical trial in which neither the investigators nor the subjects knew if naltrexone or placebo was being adminis tered. 3 The researchers administered either 50 mg of naltrexone or placebo daily on an outpatient basis to 70 alcoholdependent male veterans, predominantly African American and unemployed, who had been drinking heavily for an average of 20 years. In addition to their medication, all subjects received psychosocial therapy in the hospital that included supportive alcoholism counseling, relapse prevention therapy, and referral to Alcoholics Anonymous meetings. Primary outcome measures included selfreports of alcohol drinking and craving (i.e., the desire to drink as assessed on a 10point scale) and liver damage as determined by increased liver enzyme levels. Alcohol relapse also was assessed as a measure different from sampling alcohol, or "slipping." Craving. The naltrexonetreated subjects experienced a gradual decline in alcohol craving during the 12 weeks of the study. The placebotreated subjects, however, had higher overall levels of craving throughout the study and experienced no reduction in craving (figure 3).

Effects on Drinking.
Possibly as a conse quence of their reduced desire to drink, naltrexonetreated subjects reported less alcohol consumption than the placebo treated subjects. Although the percentage of naltrexonetreated patients who drank any alcohol during the study was equal to the percentage of placebotreated patients who drank, the naltrexonetreated patients who slipped consumed alcohol on fewer days than did placebotreated patients. Of the subjects who slipped, the placebo treated group drank alcohol on nearly four times as many days as the naltrexone treated subjects (14.0 percent of the study days versus 3.6 percent of the study days).
To support the results obtained from the subjects' selfreports of drinking, excessive alcohol consumption was as sessed by monitoring elevations in liver enzymes that signify liver damage. Al though the naltrexone and placebo groups did not differ significantly from each other, many naltrexone subjects had lower liver enzyme values.

Effects on
Relapse. An important meas ure of naltrexone's beneficial effects can be seen when looking at the loss of control over alcohol drinking, or alcohol relapse, in these patients. For research purposes, Volpicelli and colleagues defined alcohol relapse in the subjects as follows: consum ing five or more drinks on a particular drinking occasion, presenting for treatment with a blood alcohol concentration greater than 100 mg percent (legal intoxication), or consuming alcohol five or more times during the previous week.
The fivedrinksperdrinkingoccasion criterion was the most sensitive measure of relapse, because virtually every subject who met the other relapse criteria also met the fivedrink criterion. The fivedrink criterion was based on data suggesting that alcohol binges of five or more drinks for males and four or more drinks for females are associated with biopsychosocial prob lems (i.e., any type of alcoholrelated problems; Knupfer 1984). Volpicelli and colleagues' clinical data (1992) further suggest that subjects who met the relapse criteria were likely to meet other criteria for alcohol dependence, such as elevated liver enzymes; a feeling of loss of control over alcohol use; interpersonal problems; and, in the subjects who worked, occupa tional problems. In contrast, none of the subjects who drank alcohol but who did not meet relapse criteria had any biopsy chosocial problems associated with their alcohol use. Using this definition of re lapse, about onehalf of the placebotreated subjects relapsed during the 12 weeks of the study, whereas fewer than onefourth of the naltrexonetreated subjects relapsed ( figure 4).

Side Effects.
The study's psychiatrist assessed treatment side effects noticed by the subjects every 4 weeks. Of the 70 subjects enrolled, only 2 subjects with drew from the study because they were unable to tolerate the side effects. Both subjects were taking naltrexone and complained of nausea. This finding was not significant. Except for nausea, all other side effects were mild in nature and did not differ between groups.

The O'Malley Study
Another trial of naltrexone in a distinct outpatient population incorporated two different psychosocial therapies and further demonstrated the medication's effectiveness at reducing slips and pre venting alcohol relapse among people in alcoholism treatment. In this study, O'Malley and colleagues (1992) adminis tered 50 mg of naltrexone or placebo for 12 weeks to 97 subjects (72 men and 25 women), predominately white and em ployed full time.
Overall, O'Malley and colleagues found that naltrexone treatment reduced alcohol consumption and lowered relapse rates. In addition, the researchers investi gated the interaction of naltrexone with two types of psychosocial therapy. One type of therapy, coping skills therapy, taught patients strategies to cope with alcohol craving and to identify and cope with lifestyle factors that may lead to alcohol relapse (e.g., learning to manage anger or to communicate in close relation ships). The other type of therapy, support ive therapy, involved patients meeting with a nondirective therapist (i.e., one who encouraged abstinence without teaching specific coping skills) to discuss issues relating to abstinence and treatment.
Similar to the Volpicelli study (1992), O'Malley defined relapse as drinking five or more drinks on an occasion for male subjects and four or more drinks on an occasion for females. Using these defini tions, O'Malley and colleagues found that naltrexone reduced overall relapse rates among subjects by approximately onehalf. Also, subjects taking naltrexone reported drinking on only 4.3 percent of the study days, whereas placebo subjects consumed alcohol on 9.9 percent of the study days.
An interaction also appeared to occur between the use of medication and the type of psychotherapy group attended. Subjects taking naltrexone and receiving supportive therapy were less likely to sample a drink for the first time after beginning treatment than were subjects in the other treatment groups. Subjects taking naltrexone and receiving coping skills therapy, however, slipped as often as the placebo subjects but were less likely to relapse than any other group once a slip occurred.
The study by O'Malley and colleagues suggests that a program combining nal trexone treatment with coping strategies seems particularly effective in reducing alcohol relapse, alcohol craving, and loss of control over alcohol drinking.

EVIDENCE FOR NALTREXONE'S MECHANISM OF ACTION
Both clinical trials of naltrexone demon strated a significant reduction of alcohol relapse in those subjects taking naltrexone compared with subjects taking placebo. For example, nearly all the subjects taking placebo who slipped during the study went on to meet relapse criteria. In com parison, only onehalf of the subjects taking naltrexone who slipped during the study relapsed (Volpicelli et al. 1992). Although naltrexone may not reduce the risk of slipping, it appears to stop a slip from becoming a relapse. Furthermore, naltrexone seems to prevent the loss of control over alcohol consumption and the return to alcohol abuse and dependence typical of many alcoholdependent pa tients in treatment. It may do so by dimin ishing alcohol's pleasurable effects.
In Volpicelli and colleagues' (1992) clinical trial, subjects who experienced a slip during the trial were asked to report the subjective effects of alcohol and to rate the "high," or euphoria, from alcohol during their slip on a threepoint scale (from 1 to +1; see figure 5). The average rating was 0.58, implying that naltrexone treated patients experienced a decrease in their high obtained from drinking alcohol. The placebotreated patients, however, reported no change in alcohol euphoria (mean rating, +0.06) (Volpicelli et al. 1992). This suggests that the decrease in alcohol consumption in the naltrexone group was attributable to the reduction in the high normally caused by alcohol consumption. However, in this study with alcoholdependent subjects, the amount of alcohol consumed during a slip was not controlled. Because naltrexonetreated subjects also drank less alcohol than placebotreated subjects did during their slips, the diminished high may instead have been a consequence of their reduced alcohol intake. The studies with nonde pendent social drinkers reviewed below (Swift et al. in press) support naltrexone's ability to reduce alcohol's high.

Why Might Naltrexone Work?
Naltrexone may reduce alcohol craving that alcoholdependent people often feel. Alcohol dependence is characterized by a loss of control over drinking, expressed by recovering alcoholics as feeling that "1 drink is too many and 100 is not enough." Many alcoholdependent pa tients report that the more alcohol they drink, the greater their craving becomes, and they are unable to stop drinking once they begin. As discussed earlier, this vicious cycle may be initiated by alcohol induced increases in opiate receptor activi ty, leading to an increased motivation to drink alcohol. Naltrexone, by blocking opiate receptors, should disrupt this cycle by obstructing the enhanced opiate receptor activity induced by alcohol consumption.
Naltrexone also may mitigate the pleasure people experience when they drink. The animal data reviewed here suggest that alcohol is rewarding in part because of its effect on opiate receptor activity. In some people, alcohol may produce a morphinelike high. If this is true, it would be likely that these people would not experience an alcohol high while taking naltrexone.
To determine if naltrexone reduces the pleasurable effects associated with drink ing, studies must be conducted in which the amount of alcohol consumed is con sistent across all groups. Giving alcohol to recovering alcoholics raises ethical concerns; therefore, the effects of naltrex one on reducing drinking pleasure are best studied using nondependent social drinkers. In one such study, Swift and colleagues (in press) found that after a standard dose of alcohol (e.g., a 5ounce glass of wine), social drinkers who took naltrexone experienced less euphoria than the subjects who took the placebo.
Naltrexone not only reduced the plea surable effects associated with drinking, but it also increased the less desirable sedative effects of alcohol relative to the effects felt by the placebo group. Thus, although the naltrexonetreated subjects experienced the negative effects of alco hol consumption, they did not experience the positive effect of euphoria that is a motivation for drinking alcohol.
Alternately, naltrexone may interact with alcohol consumption to produce an aversive reaction, similar to the presumed mechanism for disulfiram. For example, some subjects taking naltrexone reported that following alcohol consumption they felt "hungover" or nauseous a few hours after drinking. Consequently, they did not enjoy the alcohol. In social drinkers, Swift and colleagues (in press) have reported similar results: some subjects taking naltrexone and drinking alcohol vomited. Taking naltrexone alone or consuming alcohol alone was not associ ated with vomiting. Naltrexone's effects on the alcohol "high" felt by patients who slipped (tasted alcohol during the study) are shown. Patients compared the high they experienced at this time with the high they felt from alcohol before they entered treatment. Each bar represents the average score for all patients in each group. On a scale from negative 1 to positive 1, patients given naltrexone who slipped during the study rated their alcohol high as an average of -0.58. Patients on the placebo rated the high as an average of 0.06.

CONCLUSIONS
Naltrexone has been shown in two inde pendent, doubleblind clinical trials to reduce alcohol consumption effectively in alcoholdependent patients when used in conjunction with psychosocial therapy. Alcoholdependent patients who take naltrexone show significantly reduced drinking levels and alcohol relapse and report a reduced high from alcohol. It is unlikely that any single medica tion will be effective for all alcohol dependent subjects. Further research is needed to identify "responder" subpopu lations (whose characteristics predispose them to have the most success with a certain medication) so that the appropriate pharmacological interventions for each group can be given. Additional research on the most effective dose of naltrexone in the treatment of alcohol dependence and the most effective treatment duration also should be performed before naltrex one can be widely used in clinical set tings. Even if naltrexone is found to be pharmacologically effective, a patient's motivation to refrain from drinking must be reinforced, or it is likely that poor compliance will limit naltrexone's clinical utility. The clinical studies reported here included subjects who were actively engaged in psychotherapy. Thus, naltrex one is best used as a part of a treatment program that includes psychosocial inter ventions. At this point, findings indicate that naltrexone has significant promise as a safe pharmacological adjunct in treating alcohol dependence. ■